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Adding Ipilimumab and Nivolumab to Hepatic Perfusion Triples One-Year PFS in Uveal Melanoma
In a randomised phase 2 trial, combining percutaneous hepatic perfusion with ipilimumab and nivolumab more than tripled one-year progression-free survival compared with perfusion alone — 54.7% versus 15.8% — representing about a 66% reduction in the risk of progression or death (adjusted HR 0.34, 95% CI 0.19–0.60). The result is statistically robust, though the single-centre design and small sample size warrant cautious interpretation.
What Was Studied
This trial investigated whether adding immune checkpoint blockade — specifically ipilimumab and nivolumab — to percutaneous hepatic perfusion (PHP) would improve outcomes in patients with metastatic uveal melanoma. The question is clinically important because PHP can control hepatic disease effectively but has no impact on extrahepatic spread, while checkpoint inhibitors alone show limited activity in this tumour type; combining both strategies was hypothesised to address each modality’s individual weakness.
How It Was Studied
The CHOPIN trial was a single-centre, open-label, investigator-initiated, randomised phase 2 study enrolling adults aged 18–80 with unresectable liver-only or liver-dominant metastatic uveal melanoma, WHO performance status 0–1, and no prior systemic therapy. Seventy-six eligible patients were randomly assigned 1:1 to PHP alone or PHP plus ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) given intravenously every three weeks across four doses, with no maintenance. PHP was delivered using melphalan (3 mg/kg; maximum 220 mg) at weeks 1 and 7. The primary endpoint was one-year progression-free survival in the intention-to-treat population, with a median follow-up of 24.9 months (IQR 15.4–36.0).
What Was Observed
- One-year progression-free survival was substantially higher with combination therapy: 54.7% (95% CI 36.8–69.5) versus 15.8% (95% CI 5.8–30.1) with PHP alone. The adjusted hazard ratio of 0.34 (95% CI 0.19–0.60; p=0.0002) indicates approximately 66% lower risk of disease progression or death in the combination arm — a difference that is highly unlikely to reflect chance.
- Grade 3–4 treatment-related adverse events were markedly more frequent in the combination group: occurring in 82% of patients (31 of 38) compared with 41% in the perfusion-alone group (15 of 37). The elevated toxicity stemmed from both a higher rate of severe perfusion-related events and the addition of immunotherapy-related toxicities.
- The most common severe adverse events in the combination arm included thrombocytopenia (34% vs. 14%), leukopenia (26% vs. 14%), elevated γ-glutamyl transferase (18% vs. 8%), and anaemia (13% vs. 3%), all higher than in the perfusion-only group, reflecting both haematological and hepatic stress.
- One treatment-related death occurred in the combination group, attributed to triple M syndrome — a recognised but rare complication associated with melphalan hepatic perfusion — underscoring the need for careful patient selection and experienced procedural teams.
Why This Matters
Metastatic uveal melanoma carries a poor prognosis and has historically shown very limited responsiveness to systemic immunotherapy, making effective treatment options scarce. The CHOPIN trial provides the first randomised evidence that integrating locoregional hepatic therapy with dual checkpoint blockade can meaningfully alter the disease trajectory, at least in terms of progression-free survival. This combination strategy may reframe how the research community thinks about sequencing or integrating locoregional and systemic immune-based approaches in liver-dominant solid tumour metastases more broadly.
How to Read This Result
While the progression-free survival benefit is large and statistically compelling, the single-centre design, small sample size, and open-label methodology limit the degree to which these findings can be generalised without validation in larger, multicentre studies.
Limitations
The authors acknowledge that the single-centre design restricts generalisability, and that the rarity of uveal melanoma makes large-scale multicentre replication inherently difficult to execute. Overall survival data were not yet reported as a primary endpoint, meaning the durability of the progression-free survival benefit and its translation into survival gain remain to be established.